Young injection drug users (IDU) constitute a distinctive high risk and understudied group with high rates of hepatitis C virus (HCV) infection. Our group has successfully initiated prospective research to identify and study early HCV infection in this population: we have enrolled 163 HCV antibody (anti-HCV) negative young IDU in a longitudinal study (UFO-3 Study) and identified 22 incident HCV infections, 19 of whom are being followed prospectively (Acute UFO study). Using transcription mediated amplification (TMA) testing we successfully detect acute HCV infection (10 of 22 new infections) during the seronegative window period. HCV incidence is estimated at 27.8% to 40.7% per year. 1 of 7 (14%) new genotype 1 HCV infections with completed RNA tests six months apart has spontaneously resolved infection and liver function tests (LFT) as measured by liver transaminase (ALT) levels are normal. 2 of 8 (25%) genotype 3 infections appear to be resolving. Preliminary immunological analyses have shown broad HCV-specific T cell responses in resolvers. This application seeks a 4-year renewal of NIDA R01 DAI 6017-01 to continue our investigation of immunological and viral factors related to resolution. We will continue immunological studies of the spectrum of cytotoxic T lymphocyte (CTL) responses and evolution within CTL targets ("epitopes") in early infection, to identify early correlates of viral resolution, critical for defining correlates of protective immunity and thus future vaccine development. We will now include genotype 3 infection in these analyses. We will expand our investigation of factors that may be associated with determining candidacy for early antiviral treatment. Finally, we add to this application, a distinctive new study, incorporating epidemiological and molecular virology methods to study HCV infectivity and transmission dynamics of acute HCV between young IDU in injecting and sexual partnerships using phylogenetic analyses coupled with epidemiologic data. The team of investigators collaborating on this application combines the scientific disciplines of epidemiology, immunology, molecular virology, laboratory science and the clinical disciplines of hepatology and infectious disease in this study of acute HCV infection in young IDU.